The long-term objective of this project is to elucidate the relationships among dengue virus (DENV)-specific immune responses measured before and during acute infection, DENV-specific immune responses induced by a tetravalent live-attenuated vaccine, and the clinical outcome of infection. The adaptive immune response to DENV has the potential for either positive (protective) or negative (pathologic) effects on subsequent DENV infection. We hypothesize that quantitative, qualitative, and kinetic aspects of DENVspecific immune responses all play important roles in determining the outcome of infection, and that these features of DENV-specific immunity depend on the sequence and frequency of exposure to DENV. We will address our hypotheses through the following Specific Aims: 1. Define immunodominant T cell epitopes associated with secondary DENV infection and specific HLA alleles and sequences of infection 2. Define the relationships between pre-infection DENV-specific immune responses, immune activation during infection, and clinical outcome 3. Define the relationships between pre-existing DENV-specific immune responses, immune responses to vaccination with Chimerivax-DEN (tetravalent DENV-YFV chimeric vaccine), and vaccine efficacy Identifying the features of protective and pathological immunity to DENV is of importance to advancing vaccine development and utilization.